Environmental factors explained 17 percentage points more mortality variation than genetic risk. Specifically, smoking, socioeconomic status, and physical activity showed the strongest associations with premature death, according to a recent study.
Researchers conducted a large-scale analysis of the relative contributions of environmental and genetic factors to aging and premature mortality. Their study, published in Nature Medicine, utilized data from the U.K. Biobank (n = 492,567) to perform an exposome-wide analysis of all-cause mortality and assess environmental associations with a proteomic aging clock in a subset of 45,441 participants.
The study identified 25 independent environmental exposures that were significantly linked to mortality, aging biomarkers, and disease risk factors. Researchers found that polygenic risk scores for 22 major diseases explained less than 2 percentage points of additional mortality variation, whereas environmental factors accounted for an additional 17 percentage points. While genetic predisposition contributed more substantially to diseases such as dementia and breast, prostate, and colorectal cancers (10.3%–26.2% of variation), environmental exposures played a dominant role in conditions that affect the lungs, heart, and liver (5.5%–49.4%).
To address confounding, researchers led by M. Austin Argentieri of Nuffield Department of Population Health, University of Oxford in Oxford, U.K., conducted a hierarchical clustering analysis to isolate independent environmental risk factors. The most significant risk factors for increased mortality included current smoking (hazard ratio [HR] > 1.4), living in council housing (HR > 1.4), and experiencing frequent fatigue (HR > 1.4). Protective factors included higher household income (HR < 0.8), employment (HR < 0.8), and living with a partner (HR < 0.8). The study also found that Black, Asian, and other non-White ethnic groups had lower mortality risk compared with White participants.
Further analysis examined the association of these 25 exposures with 25 age-related diseases and 25 biochemical markers of aging. On average, each exposure correlated with 22 biomarkers, affecting metabolic, inflammatory, and cardiovascular pathways. Smoking was associated with 21 of the 25 diseases, while socioeconomic factors, physical activity, and sleep patterns were linked to multimorbidity.
The findings indicate that environmental factors explain a greater proportion of mortality risk than genetic predisposition. Further, they suggest that modifiable environmental risk factors—such as smoking, socioeconomic conditions, and physical activity—are strongly associated with premature mortality and age-related diseases, though further causal research is required to determine the impact of targeted interventions.
The researchers declared no competing interests.
